PROJECT SUMMARY/ABSTRACT Intensive care provides lifesaving monitoring and intervention. However, extensive literature reports that intensive care unit (ICU) survivors, particularly older patients, too often experience significant deficits following discharge that impair quality of life for at least 1 year after discharge. Delirium, which presents in 30-80% of ICU patients depending upon specific population, has been associated with worse outcomes, including cognitive dysfunction and progression to dementia, and therefore has been a focus of intervention studies to improve ICU survivor outcomes. The majority of these studies focus on two areas- modifying the sedation regime and promoting early mobility. While important, these studies do not target the underlying mechanism that leads to delirium. The pathophysiologic underpinnings of delirium are not well understood and there are no known efficacious treatments. This proposal focuses on increasing understanding of the complex pathophysiologic mechanisms, and specifically persistent inflammation, contributing to ICU delirium and the individual variability contributing to this process. While all ICU patients are at risk, not all individuals experience ICU delirium and older individuals are more likely to develop delirium. Identifying mechanisms that contribute to delirium can provide information crucial to decreasing its? frequency and improving the poor outcomes in ICU survivors. We hypothesize that there is variable inflammatory gene methylation during critical illness influenced by age, sex and medical condition and, in addition, distinct inflammatory gene methylation profiles characteristic to patients who develop ICU delirium. Identification of these profiles will clarify time dependent changes in inflammatory status important for brain function. The aims of this project will identify changes in inflammatory gene methylation during the first 7 days after ICU admission in subjects of different age and sex and with different medical diagnoses, as well as the specific changes occurring before and during ICU delirium, while controlling for relevant cell counts. Additionally we will quantify gene product (protein) in serum of a subset of the population to explore the relationship between inflammatory gene methylation and associated inflammatory proteins. This project capitalizes on the experience and expertise of a multi-disciplinary investigative team including representation from the fields of nursing, genetics, neuropsychology, statistics and critical care medicine. The overall goal of this project is to clarify one possible source of genetic variability contributing to a persistent inflammatory state common in delirium in ICU patients.